Pharmaceutical formulations for dry powder inhalers in the form of hard-pellets

ABSTRACT

The invention provides a formulation to be administered as dry powder for inhalation suitable for efficacious delivery of active ingredients into the low respiratory tract of patients suffering of pulmonary diseases such as asthma. In particular, the invention provides a formulation to be administered as dry powder for inhalation freely flowable, which can be produced in a simple way, physically and chemically stable and able of delivering either accurate doses and high fine particle fraction of low strength active ingredients by using a high- or medium resistance device.

PRIOR ART

[0001] Inhalation anti-asthmatics are widely used in the treatment ofreversible airway obstruction, inflammation and hyperresponsiveness.

[0002] Presently, the most widely used systems for inhalation therapyare the pressurised metered dose inhalers (MDIs) which use a propellantto expel droplets containing the pharmaceutical product to therespiratory tract.

[0003] However, despite their practicality and popularity, MDIs havesome disadvantages:

[0004] i) droplets leaving the actuator orifice could be large or havean extremely high velocity resulting in extensive oropharyngealdeposition to the detriment of the dose which penetrates into the lungs;the amount of drug which penetrates the bronchial tree may be furtherreduced by poor inhalation technique, due to the common difficulty ofthe patient to synchronise actuation form the device with inspiration;

[0005] ii) chlorofluorocarbons (CFCs), such as freons contained aspropellants in MDIs, are disadvantageous on environmental grounds asthey have a proven damaging effect on the atmospheric ozone layer.

[0006] Dry powder inhalers (DPIs) constitute a valid alternative to MDIsfor the administration of drugs to airways. The main advantages of DPIsare:

[0007] i) being breath-actuated delivery systems, they do not requireco-ordination of actuation since release of the drug is dependent on thepatient own inhalation;

[0008] ii) they do not contain propellants acting as environmentalhazards;

[0009] iii) the velocity of the delivered particles is the same or lowerthan that of the flow of inspired air, so making them more prone tofollow the air flow than the faster moving MDI particles, therebyreducing upper respiratory tract deposition.

[0010] DPIs can be Divided into Two Basic Types:

[0011] i) single dose inhalers, for the administration of pre-subdividedsingle doses of the active compound;

[0012] ii) multidose dry powder inhalers (MDPIs), either withpre-subdivided single doses or pre-loaded with quantities of activeingredient sufficient for multiple doses; each dose is created by ametering unit within the inhaler.

[0013] On the basis of the required inspiratory flow rates (1/min) whichin turn are strictly depending on their design and mechanical features,DPI's are also divided in:

[0014] i) low-resistance devices (>90/min);

[0015] ii) medium-resistance devices (about 60 1/min);

[0016] iii) high-resistance devices (about 30 1/min).

[0017] The reported flow rates refer to the pressure drop of 4 KPa(KiloPascal) in accordance to the European Pharmacopoeia (Eur Ph).

[0018] Drugs intended for inhalation as dry powders should be used inthe form of micronised powder so they are characterised by particles offew microns (μm) particle size. Said size is quantified by measuring acharacteristic equivalent sphere diameter, known as aerodynamicdiameter, which indicates the capability of the particles of beingtransported suspended in an air stream. Hereinafter, we consider asparticle size the mass median aerodynamic diameter (MMAD) whichcorresponds to the aerodynamic diameter of 50 percent by weight of theparticles. Respirable particles are generally considered to be thosewith diameters from 0.5 to 6 μm, as they are able of penetrating intothe lower lungs, i.e. the bronchiolar and alveolar sites, whereabsorption takes place. Larger particles are mostly deposited in theoropharyngeal cavity so they cannot reach said sites, whereas thesmaller ones are exhaled.

[0019] Although micronisation of the active drug is essential fordeposition into the lower lungs during inhalation, it is also known thatthe finer are the particles, the stronger are the cohesion forces.Strong cohesion forces hinder the handling of the powder during themanufacturing process (pouring, filling). Moreover they reduce theflowability of the particles while favouring the agglomeration and/oradhesion thereof to the walls. In multidose DPI's, said phenomena impairthe loading of the powder from the reservoir to the aerosolizationchamber, so giving rise to handling and metering accuracy problems.

[0020] Poor flowability is also detrimental to the respirable fractionof the delivered dose being the active particles unable to leave theinhaler and remaining adhered to the interior of the inhaler or leavingthe inhaler as large agglomerates; agglomerated particles, in turn,cannot reach the bronchiolar and alveolar sites of the lungs. Theuncertainty as to the extent of agglomeration of the particles betweeneach actuation of the inhaler and also between inhalers and differentbatches of particles, leads to poor dose reproducibility as well.

[0021] In the prior art, one possible method of improving the flowingproperties of these powders is to agglomerate, in a controlled manner,the micronised particles to form spheres of relatively high density andcompactness. The process is termed spheronisation while the roundparticles formed are called pellets. When, before spheronisation, theactive ingredient is mixed with a plurality of fine particles of one ormore excipient, the resulting product has been termed as soft pellets.

[0022] Otherwise powders for inhalation could be formulated by mixingthe micronised drug with a carrier material (generally lactose,preferably αlactose monohydrate) consisting of coarser particles to giverise to so-called ‘ordered mixtures’.

[0023] However, either ordered mixtures and pellets should be able toeffectively release the drug particles during inhalation, in order toallow them to reach the target site into the lungs.

[0024] At this regard, it is well known that the interparticle forceswhich occur between the two ingredients in the ordered mixtures may turnout to be too high thus preventing the separation of the micronised drugparticles from the surface of the coarse carrier ones during inhalation.The surface of the carrier particles is, indeed, not smooth but hasasperities and clefts, which are high energy sites on which the activeparticles are preferably attracted to and adhere more strongly. Inaddition, ordered mixtures consisting of low strength active ingredientscould also face problems of uniformity of distribution and hence ofmetering accurate doses.

[0025] On the other hand, soft pellets may reach a so high internalcoherence as to compromise their breaking up into the small particlesduring inhalation; such drawback could be regarded as a particularcritical step when high-resistance dry powder inhalers are used. Withsaid inhalers, less energy is indeed available for breaking up thepellets into the small primary particles of the active ingredient. Thesoft pellets may also face some problems of handling during filling anduse of the inhalers.

[0026] In consideration of all problems and disadvantages outlined, itwould be highly advantageous to provide a formulation aimed atdelivering low strength active ingredients after inhalation with a DPIdevice, preferably a high-resistance one and exhibiting: i) gooduniformity of distribution of the active ingredient; ii) small drugdosage variation (in other words, adequate accuracy of the delivereddoses); iii) good flowability; iv) adequate physical stability in thedevice before use; v) good performance in terms of emitted dose and fineparticle fraction (respirable fraction).

[0027] Another requirement for an acceptable formulation is its adequateshelf-life.

[0028] It is known that the chemical compounds can undergochemico-physical alterations such. as amorphisation, when subjected tomechanical stresses. Amorphous or partially amorphous materials, inturn, absorb water in larger amounts than crystalline ones (Hancock etal. J. Pharm. Sci. 1997, 86, 1-12) so formulations containing activeingredients, whose chemical stability is particularly sensitive to thehumidity content, will benefit during their preparation by the use of aslow as possible energy step treatment.

[0029] Therefore, it would be highly advantageous to provide a processfor preparing said formulation in which a low energy step is envisionedduring the incorporation of the active ingredient to the mixture in sucha way to ensure adequate shelf life of the formulation suitable forcommercial distribution, storage and use.

OBJECT OF THE INVENTION

[0030] It is an object of the invention to provide a formulation to beadministered as dry powder for inhalation suitable for efficaciousdelivery of low strength active ingredients into the low respiratorytract of patients suffering of pulmonary diseases such as asthma. Inparticular , it is an object of the invention to provide a formulationto be administered as dry powder for inhalation freely flowable, whichcan be produced in a simple way, physically and chemically stable andable of delivering either accurate doses and high fine particle fractionof the following active ingredients: long acting β2-agonists belongingto the formula sketched below

[0031] wherein R is preferably 1-formylamino-2-hydroxy-phen-5-yl(formoterol) or 8-hydroxy-2(1H)-quinolinon-5-yl (TA 2005) and itsstereoisomers and their salts;

[0032] a corticosteroid selected from budesonide and its epimers,preferably its 22R epimer;

[0033] their mixture and their combination with other active ingredientssuch as for example beclometasone dipropionate

[0034] According to a first embodiment of the invention there isprovided a powdery formulation comprising: i) a fraction of fineparticle size constituted of a mixture of a physiologically acceptableexcipient and magnesium stearate, the mixture having a mean particlesize of less than 35 μm; ii) a fraction of coarse particles constitutedof a physiologically acceptable carrier having a particle size of atleast 90 μm , said mixture being composed of 90 to 99 percent by weightof the particles of excipient and 1 to 10 percent by weight of magnesiumstearate and the ratio between the fine excipient particles and thecoarse carrier particles being between 1:99 and 40:60 percent by weight;and the said mixture having been further mixed with the activeingredients mentioned above in micronised form or combination thereof.

[0035] In a preferred embodiment of the invention, the magnesiumstearate particles partially coat the surface of either the excipientparticles and the coarse carrier particles. Said feature could beachieved by exploiting the peculiar film forming properties of suchwater-insoluble additive, as also reported in the co-pending applicationWO 00/53157 of Chiesi. The coating can be established by scanningelectron microscope and the degree of coating can be evaluated by meansof the image analysis method.

[0036] It has been found indeed that the single features of addingeither of a fraction with a fine particle size of the physiologicallyacceptable excipient or magnesium stearate is not enough forguaranteeing high fine particle doses of the aforementioned activeingredients upon inhalation in particular by a high-resistance device.For significantly improving the aerosol performances, it is necessarythat both said excipient with a suitable particle size fraction shouldbe present in the formulation and that the magnesium stearate particlesshould, at least partially, coat the surface of either the excipient andthe coarse carrier particles.

[0037] Moreover, it has been found that the particle size of thephysiologically acceptable excipient, the main component of the mixturei) is of particular importance and that the best results in terms ofaerosol performances are achieved when its particle size is less than 35μm, preferably less than 30, more preferably less than 20, even morepreferably less than 15 μm.

[0038] In a more preferred embodiment , the formulation of the inventionis in the form of ‘hard pellets’ and they are obtained by subjecting themixture to a spheronisation process.

[0039] By the term of ‘hard pellets’ we mean spherical or semi-sphericalunits whose core is made of coarse particles. The term has been coinedfor distinguishing the formulation of the invention from the softpellets of the prior art which are constituted of only microfineparticles (WO 95/24889, GB 1520247, WO 98/31353).

[0040] By the term ‘spheronisation’ we mean the process of rounding offof the particles which occurs during the treatment.

[0041] In an even more preferred embodiment of the invention, the coarsecarrier particles have a particle size of at least 175 μm as well as ahighly fissured surface. A carrier of the above mentioned particle sizeis particularly advantageous when the fine excipient particlesconstitute at least the 10 percent by weight of the final formulation.

[0042] It has been found that, whereas formulations containingconventional carriers and having fine particle contents of above 10%tend to have poor flow properties, the formulations according to theinvention have adequate flow properties even at fines contents (that iscontents of active particles and of fine excipient particles) of up to40 percent by weight.

[0043] The prior art discloses several approaches for improving theflowability properties and the respiratory performances of low strengthactive ingredients. WO 98/31351 claims a dry powder compositioncomprising formoterol and a carrier substance, both of which are infinely divided form wherein the formulation has a poured bulk density offrom 0.28 to 0.38 g/ml. Said formulation is in the form of soft pelletand does not contain any additive.

[0044] EP 441740 claims a process and apparatus thereof foragglomerating and metering non-flowable powders preferably constitutedof micronised formoterol fumarate and fine particles of lactose (softpellets).

[0045] Furthermore several methods of the prior art were generallyaddressed at improving the flowability of powders for inhalation and/orreducing the adhesion between the drug particles and the carrierparticles.

[0046] GB 1,242,211, GB 1,381,872 and GB 1,571,629 disclosepharmaceutical powders for the inhalatory use in which the microniseddrug (0.01-10 μm) is respectively mixed with carrier particles of sizes30 to 80 μm, 80 to 150 μm, and less than 400 μm wherein at least 50% byweight of which is above 30 , m.

[0047] WO 87/05213 describes a carrier, comprising a conglomerate of asolid water-soluble carrier and a lubricant, preferably 1% magnesiumstearate, for improving the technological properties of the powder insuch a way as to remedy to the reproducibility problems encounteredafter the repeated use of a high resistance inhaler device.

[0048] WO 96/02231 claims a mixture characterised in that the micronisedactive compound is mixed with rough carrier particles having a particlesize of 400 μm to 1000 μm. According to a preferred embodiment of theinvention, the components are mixed until the carrier crystals arecoated with the fine particles (max. for 45 minutes). No example eitherwith auxiliary additives and/or with low strength active ingredient isreported.

[0049] EP 0,663,815 claims the addition of finer particles (<10 μm) tocoarser carrier particles (>20 μm) for controlling and optimising theamount of delivered drug during the aerosolisation phase.

[0050] WO 95/11666 describes a process for modifying the surfaceproperties of the carrier particles by dislodging any asperities in theform of small grains without substantially changing the size of theparticles. Said preliminary handling of the carrier causes themicronised drug particles to be subjected to weaker interparticleadhesion forces.

[0051] In WO 96/23485, carrier particles are mixed with an anti-adherentor anti-friction material consisting of one or more compounds selectedfrom amino acids (preferably leucine); phospholipids or surfactants; theamount of additive and the process of mixing are preferably chosen insuch a way as to not give rise to a real coating. It appears that thepresence of a discontinuous covering as opposed to a “coating” is animportant and advantageous feature. The carrier particles blended withthe additive are preferably subjected to the process disclosed in WO95/11666.

[0052] Kassem (London University Thesis 1990) disclosed the use ofrelatively high amount of magnesium stearate (1.5%) for increasing the‘respirable’ fraction. However, the reported amount is too great andreduces the mechanical stability of the mixture before use.

[0053] WO 00/28979 is addressed to the use of small amounts of magnesiumstearate as additive for improving the stability to the humidity of drypowder formulations for inhalation.

[0054] WO 00/33789 refers to an excipient powder for inhalable drugscomprising a coarse first fraction (with at least 80% by weight having aparticle size of at least 10 μm), a fine second fraction (with at least90% by weight having a particle size of no more than 10 μm) and aternary agent which is preferably a water-soluble surface-active agentwith a preference for leucine.

[0055] In none of aforementioned documents the features of theformulation of the invention are disclosed and none of the teachingtherein disclosed contributes to the solution of the problem accordingto the invention. All the attempts of obtaining stable powderformulations of low strength active ingredients endowed of goodflowability and high fine particle fraction according to some of theteaching of the prior art, for example by preparation of orderedmixture, addition of a fine fraction, mere addition of additives, wereindeed unsuccessful as demonstrated by the examples reported below. Inparticular, in the prior art it often occurred that the solutionsproposed for a technical problem (i.e. improving dispersion of the drugparticles) was detrimental to the solution of another one (i.e.improving flowability, mechanical stability) or vice versa.

[0056] On the contrary, the formulation of the invention shows eitherexcellent Theological properties and physical stability and goodperformances in terms of fine particle fraction , preferably more than40%. The cohesiveness between the partners has been indeed adjusted insuch a way as to give sufficient adhesion force to hold the activeparticles to the surface of the carrier particles during manufacturingof the dry powder and in the delivery device before use, but to allowthe effective dispersion of the active particles in the respiratorytract even in the presence of a poor turbulence as that created byhigh-resistance devices.

[0057] Contrary to what has been stated in the prior art (EP 441740), inthe formulation of the invention the presence of an additive withlubricant properties such as magnesium stearate, in a small amount, doesnot compromise the integrity of the pellets before use.

[0058] According to a second embodiment of the invention there are alsoprovided processes for making the formulation of the invention, in sucha way as that the magnesium stearate particles partially coat thesurface of either the excipient particles and the coarse carrierparticles with a degree of coating that can vary depending on the amountand particle size of the fine fraction and, in any case, is of at least5%, preferably at least 15%.

[0059] According to a particular embodiment, there is provided a processincluding the steps of: i) co-micronising the excipient particles andthe magnesium stearate particles such that to reduce their particle sizebelow 35 μm, and contemporaneously making the additive particlespartially coating the surface of the excipient particles; ii)spheronising by mixing the resulting mixture with the coarse carrierparticles such that mixture particles adhere to the surface of thecoarse carrier particles; iii) adding by mixing the active particles tothe spheronised particles.

[0060] According to a further particular embodiment of the inventionthere is provided another process, said process including the steps of:i) mixing the excipient particles in the micronised form and themagnesium stearate particles in such a way as to make the additiveparticles partially coating the surface of the excipient particles; ii)spheronising by mixing the resulting mixture with the coarse carrierparticles such that mixture particles adhere to the surface of thecoarse carrier particles; iii) adding by mixing the active particles tothe spheronised particles.

[0061] When the coarse carrier particles have a particle size of atleast 175 μm and in a preferred embodiment a highly fissured surface,the formulation of the invention could also be prepared by: i) co-mixingthe coarse carrier particles, magnesium stearate and the fine excipientparticles for not less than two hours;

[0062] ii) adding by mixing the active particles to the mixture.

[0063] It has been indeed found that the particles need to be processedfor at least two hours in order to either have a good fine particlefraction (respirable fraction) and no problem of sticking during thepreparation.

[0064] In all process claimed, contrary to the prior art (WO 98/31351),the active ingredient is uniformly incorporated in the mixture by simplemixing so avoiding any potential mechanical stress which may disturb thecristallinity of its particles.

[0065] Advantageously, the coarse and fine carrier particles may beconstituted of any pharmacologically acceptable inert material orcombination thereof; preferred carriers are those made of crystallinesugars, in particular lactose; the most preferred are those made ofα-lactose monohydrate. Advantageously the diameter of the coarse carrierparticles is at least 100 μm, more advantageously at least 145 μm,preferably at least 175 μm, more preferably between 175 and 400 μm, evenmore preferably between 210 and 355 μm.

[0066] When the diameter of the coarse carrier particles is at least 175μm, the carrier particles have preferably a relatively highly fissuredsurface, that is, on which there are clefts and valleys and otherrecessed regions, referred to herein collectively as fissures.

[0067] The expression “relatively highly fissured” is used herein tomean that the ratio of a theoretical envelope volume of the particles,as calculated from the envelope of the particles, to the actual volumeof the particles, that is, the volume defined by the actual surface ofthe particles (that ratio hereafter being referred to as the “fissureindex”), is at least 1.25. The theoretical envelope volume may bedetermined optically, for example, by examining a small sample of theparticles using an electron microscope. The theoretical envelope volumeof the particles may be estimated via the following method. An electronmicrograph of the sample may be divided into a number of grid squares ofapproximately equal populations, each containing a representative sampleof the particles. The population of one or more grids may then beexamined and the envelope encompassing each of the particles determinedvisually as follows. Measure the Feret's diameter for each of theparticles with respect to a fixed axis . The Feret's diameter forparticles within a grid is measured relative to a fixed axis of theimage, typically at least ten particles are measured for their Feret'sdiameter. Feret's diameter is defined as the length of the projection ofa particle along a given reference line as the distance between theextreme left and right tangents that are perpendicular to the referenceline. A mean Feret's diameter is derived. A theoretical mean envelopevolume may then be calculated from this mean diameter to give arepresentative value for all the grid squares and thus the whole sample.Division of that value by the number of particles gives the mean valueper particle. The actual volume of the particles may then be calculatedas follows. The mean mass of a particle is calculated as follows. Take asample of approximately 50 mg, record the precise weight to 0.1 mg .Then by optical microscopy determine the precise number of particles inthat sample. The mean mass of one particle can then be determined.Repeat this five times to obtain a mean value of this mean.

[0068] Weigh out accurately a fixed mass of particles (typically 50 g),calculate the number of particles within this mass using the above meanmass value of one particle. Immerse the sample of particles in a liquidin which the particles are insoluble and, after agitation to removetrapped air, measuring the amount of liquid displaced. From thiscalculate the mean actual volume of one particle.

[0069] The fissure index is advantageously not less than 1.5, and is,for example, 2 or more.

[0070] An alternative method of determining whether carrier particleshave appropriate characteristics is to determine the rugositycoefficient. The “rugosity coefficient” is used to mean the ratio of theperimeter of a particle outline to the perimeter of the “convex hull”.This measure has been used to express the lack of smoothness in theparticle outline. The “convex hull” is defined as a minimum envelopingboundary fitted to a particle outline that is nowhere concave. (See “TheShape of Powder-Particle Outlines” A. E. Hawkins, Wiley 1993). The“rugosity coefficient” may be calculated optically as follows. A sampleof particles should be identified from an electron micrograph asidentified above. For each particle the perimeter of the particleoutline and the associated perimeter of the “convex hull” is measured toprovide the “rugosity coefficient”. This should be repeated for at leastten particles to obtain a mean value. The mean “rugosity coefficient” isat least 1.25.

[0071] The additive is magnesium stearate. Advantageously, the amount ofmagnesium stearate in the final formulation is comprised between atleast 0.02 and not more than 1.5 percent by weight (which equates to 1.5g per 100 g of final formulation), preferably at least 0.05 and not morethan 1.0 percent by weight, more preferably between 0.1 and not morethan 0.6 percent by weight, even more preferably between 0.2 and 0.4percent by weight.

[0072] According to the invention the fraction with a fine particle sizeis composed of 90 to 99 percent by weight of the physiologicallyacceptable excipient and 1 to 10 percent by weight of magnesium stearateand the ratio between the fraction of fine particle size and thefraction of coarse carrier particle is comprised between 1:99 and 40:60percent by weight, preferably between 5:95 and 30:70 percent by weight,even more preferably between 10:90 and 20:80 percent by weight.

[0073] In a preferred embodiment of the invention, the fraction with afine particle size is composed of 98 percent by weight of α-lactosemonohydrate and 2 percent by weight of magnesium stearate and the ratiobetween the fraction with a fine particle size and the coarse fractionmade of α-lactose monohydrate particles is 10:90 percent by weight,respectively.

[0074] Advantageously the formulation of the invention has an apparentdensity before settling of at least 0.5 g/ml, preferably from 0.6 to 0.7g/ml and a Carr index of less than 25, preferably less than 15.

[0075] In one of the embodiment of the invention, the excipientparticles and magnesium stearate particles are co-micronised by milling,advantageously in a ball mill for at least two hours, preferably untilthe final particle size of the mixture is less than 35 μm, preferablyless than 30 μm, more preferably less than 15 μm. In a more preferredembodiment of the invention the particles are co-micronised by using ajet mill.

[0076] Alternatively, the mixture of the excipient particles with astarting particle size less than 35 μm, preferably less than 30 μm, morepreferably less than 15 μm, with the magnesium stearate particles willbe prepared by mixing the components in a high-energy mixer for at least30 minutes, preferably for at least one hour, more preferably for atleast two hours.

[0077] In a general way, the person skilled in the art will select themost proper size of the fine excipient particles either by sieving or bysuitably adjusting the time of co-milling.

[0078] The spheronisation step will be carried out by mixing the coarsecarrier particles and the fine particle fraction in a suitable mixer,e.g. tumbler mixers such as Turbula, rotary mixers or instant mixer suchas Diosna for at least 5 minutes, preferably for at least 30 minutes,more preferably for at least two hours, even more preferably for fourhours. In a general way, the person skilled in the art will adjust thetime of mixing and the speed of rotation of the mixer to obtainhomogenous mixture.

[0079] When the formulation of the invention is prepared by co-mixingthe coarse carrier particles, magnesium stearate and the fine excipientparticles all together, the process is advantageously carried out in asuitable mixer, preferably in a Turbula mixer for at least two hours,preferably for at least four hours.

[0080] The ratio between the spheronised carrier and the drug (theactive ingredient) will depend on the type of inhaler device used andthe required dose.

[0081] The mixture of the spheronised carrier with the active particleswill be prepared by mixing the components in suitable mixers like thosereported above.

[0082] Advantageously, at least 90% of the particles of the drug have aparticle size less than 10 μm, preferably less than 6 μm.

[0083] The process of the invention is illustrated by the followingexamples.

EXAMPLE 1 Hard-Pellet Formulation Containing Coarse Lactose (CapsuLac212-355 μm), a Micronized Pre-Blend Lactose/Magnesium Stearate MixtureObtained by Jet Milling and Formoterol Fumarate as Active Ingredient

[0084] a) Preparation of the Formulation

[0085] α-Lactose monohydrate SpheroLac 100 (Meggle EP D30) with astarting particle size of 50 to 400 μm (d(v, 0.5) of about 170, m) andmagnesium stearate with a starting particle size of 3 to 35 μm (d(v,0.5) of about 10 μm) in the ratio 98:2 percent by weight were co-milledin a jet mill apparatus. At the end of the treatment, a significantreduction of the particle size was observed (blend A). 85 percent byweight of α-lactose monohydrate CapsuLac (212-355 μm) was placed in a240 ml stainless steel container, then 15 percent by weight of blend Awas added. The blend was mixed in a Turbula mixer for 2 hours at 42r.p.m (blend B).

[0086] Micronised formoterol fumarate was added to the blend B and mixedin a Turbula mixer for 10 mins at 42 r.p.m. to obtain a ratio of 12 μgof active to 20 mg of carrier; the amount of magnesium stearate in thefinal formulation is 0.3 percent by weight. The final formulation (hardpellet formulation) was left to stand for 10 mins then transferred toamber glass jar.

[0087] b) Characterisation of the micronised mixture (blend A)

[0088] The micronized mixture (blend A) was characterised by particlesize analysis (Malvern analysis), water contact angle and degree ofmolecular surface coating calculated according to Cassie et al. inTransaction of the Faraday Society 40; 546,1944.

[0089] The results obtained are reported in Table 1. TABLE 1 Micronisedmixture (blend A) Particle size distribution (μm) Malvern d (v, 0.1)1.58 d (v, 0.5) 4.19 d (v, 0.9) 9.64 Water contact angle   40° Degree ofcoating   15% *

[0090] c) Chemical and technological characterisation of the hard-pelletformulation

[0091] The formulation mixture was characterised by itsdensity/flowability parameters and uniformity of distribution of theactive ingredient. The apparent volume and apparent density were testedaccording to the method described in the European Pharmacopoeia (Eur.Ph.). Powder mixtures (100 g) were poured into a glass graduatedcylinder and the unsettled apparent volume V₀ is read; the apparentdensity before settling (dv) was calculated dividing the weight of thesample by the volume V₀ After 1250 taps with the described apparatus,the apparent volume after settling (V₁₂₅₀) is read and the apparentdensity after settling (ds) was calculated.

[0092] The flowability properties were tested according to the methoddescribed in the Eur. Ph. Powder mixtures (about 110 g) were poured intoa dry funnel equipped with an orifice of suitable diameter that isblocked by suitable mean. The bottom opening of the funnel is unblockedand the time needed for the entire sample to flow out of the funnelrecorded. The flowability is expressed in seconds and tenths of secondsrelated to 100 g of sample. The flowability was also evaluated from theCarr's index calculated according to the following formula:${{Carr}^{'}s\quad {{index}(\%)}} = {\frac{{s} - {v}}{s} \times 100}$

[0093] A Carr index of less than 25 is usually considered indicative ofgood flowability characteristics. The uniformity of distribution of theactive ingredient was evaluated by withdrawing 10 samples, eachequivalent to about a single dose, from different parts of the blend.The amount of active ingredient of each sample was determined byHigh-Performance Liquid Chromatpgraphy (HPLC).

[0094] The results are reported in Table 2. TABLE 2 Chemical andTechnological Parameters of the hard pellet formulation Apparentvolume/density App. volume (V₀) before settling  156 ml App. density(d_(v)) before settling 0.64 g/ml App. volume (V₁₂₅₀) after settling 138 ml App. density (d_(s)) after settling 0.73 g/ml Flowability Flowrate through 4 mm Ø  152 s/100 g Carr Index   12 Uniformity ofdistribution of active ingredient Mean Value 12.1 μg RSD  2.2%

[0095] d) Determination of the Aerosol Performances.

[0096] An amount of powder for inhalation was loaded in a multidose drypowder inhaler (Pulvinal®—Chiesi Pharmaceutical SpA, Italy).

[0097] The evaluation of the aerosol performances was performed by usinga modified Twin Stage Impinger apparatus, TSI (Apparatus of type A forthe aerodynamic evaluation of fine particles described in FU IX, 4°supplement 1996). The equipment consists of two different glasselements, mutually connected to form two chambers capable of separatingthe powder for inhalation depending on its aerodynamic size; thechambers are referred to as higher (stage 1) and lower (stage 2)separation chambers, respectively. A rubber adaptor secures theconnection with the inhaler containing the powder. The apparatus isconnected to a vacuum pump which produces an air flow through theseparation chambers and the connected inhaler. Upon actuation of thepump, the air flow carries the particles of the powder mixture, causingthem to deposit in the two chambers depending on their aerodynamicdiameter. The apparatus used were modified in the Stage 1 Jet in orderto obtained an aerodynamic diameter limit value, dae, of 5 μm at an airflow of 30 1/min, that is considered the relevant flow rate forPulvinal® device. Particles with higher dae deposit in Stage 1 andparticles with lower dae in Stage 2. In both stages, a minimum volume ofsolvent is used (30 ml in Stage 2 and 7 ml in Stage 1) to preventparticles from adhering to the walls of the apparatus and to promote therecovery thereof.

[0098] The determination of the aerosol performances of the mixtureobtained according to the preparation process a) was carried out withthe TSI applying an air flow rate of 30 1/min for 8 seconds.

[0099] After nebulization of 10 doses, the Twin Stage Impinger wasdisassembled and the amounts of drug deposited in the two separationchambers were recovered by washing with a solvent mixture, then dilutedto a volume of 100 and 50 ml in two volumetric flasks, one for Stage 1and one for Stage 2, respectively. The amounts of active ingredientcollected in the two volumetric flasks were then determined byHigh-Performance Liquid Chromatography (HPLC). The following parameters,were calculated: i) the shot weight as mean expressed as mean andrelative standard deviation (RSD) ii) the fine particle dose (FPD whichis the amount of drug found in stage 2 of TSI; iii) the emitted dosewhich is the amount of drug delivered from the device recovered in stage1 +stage 2; iv) the fine particle fraction (FPF) which is the percentageof the emitted dose reaching the stage 2 of TSI.

[0100] The results in terms of aerosol performances are reported inTable 3. TABLE 3 Aerosol performances Shot weight Emitted dose FPD FPFmg (%) μg μg % 20.0 (7.8) 9.40 4.44 47.2

[0101] The formulation of the invention shows very good flow propertiesas demonstrated by the Carr index; this parameter is very important toobtain consistency of the delivered dose when a multi-dose dry powderinhalers with powder reservoir is used. The aerosol performance of theformulation is very good as well with about 50% of the drug reaching thestage 2 of the TSI.

EXAMPLE 2 Hard-Pellet Formulation Containing Coarse Lactose (CapsuLac212-355, m), a Micronized Pre-blend Lactose/Magnesium Stearate MixtureObtained by Ball Milling and Formoterol Fumarate as Active Ingredient

[0102] Blend A was prepared as described in the Example 1 but usingα-lactose monohydrate SorboLac 400 with a starting particle size below30 μm ( d(v, 0.5) of about 10 μm) and carrying out the co-micronisationin a ball milling apparatus for 2 hours.

[0103] Blend B was prepared according to the Example 1 but after mixingfor 6 mins and then screening through a 355 μm sieve.

[0104] The hard pellet final formulation was prepared according to theExample 1.

[0105] The particle size distribution, the water contact angle and thedegree of coating for the micronized mixture (blend A), and theuniformity of distribution of the active ingredient for the finalformulation (blend B), determined as previously described, are reportedin Table

[0106] Analogous results were achieved after preparing blend B by mixingfor 4 hours without screening through a sieve. TABLE 4 Characterisationof blends A and B Micronised mixture (blend A) Particle sizedistribution (μm) Malvern d (v, 0.1)  0.72 μm d (v, 0.5)  2.69 μm d (v,0.9) 21.98 μm water contact angle   52° degree of coating   25% Finalformulation (blend B) Uniformity of distribution of the activeingredient Mean = 11.84 μg  RSD = 1.83%

[0107] The in-vitro performances, determined as previously described,are reported in Table 5. TABLE 5 Aerosol performances Shot weightEmitted dose FPD FPF mg (%) μg μg % 20.8 (6.9) 8.57 4.28 49.9

[0108] As it can be appreciated from the results, also such formulationshow excellent characteristics either in terms of flowability propertiesand in terms of aerosol performances.

EXAMPLE 3 Determination of the Suitable Amount of Magnesium Stearate tobe added in the Formulation

[0109] Samples of pre-blends were prepared as described in Example 2 ina ball milling apparatus for 2 hours using α-Lactose monohydrateSorboLac 400 (Meggle microtose) with a starting particle size below 30μm (d(v, 0.5) of about 10 μm) and magnesium stearate with a startingparticle size of 3 to 35 μm (d(v, 0.5) of about 10 μm) in the ratio98:2, 95:5 and 90:10 percent by weight (blends A).

[0110] Blends B and the hard pellet final formulation were prepared aspreviously described; the amount of magnesium stearate in the finalformulations turns out to be 0.3, 0.75 and 1.5 percent by weight,respectively. The uniformity of distribution of active ingredient andthe in-vitro aerosol performance were determined as previouslydescribed. The results obtained are reported in Table 6. TABLE 6Uniformity of distribution and in-vitro aerosol performances Mg stearateMg stearate Mg stearate 0.3% 0.75% 1.5% Content uniformity Mean (μg)11.84 — — RSD (%) 1.83 — — Shot weight Mean (mg) 20.8 24.7 23.0 RSD (%)6.9 6.5 2.4 Emitted dose (μg) 8.57 10.1 11.1 FPD (μg) 4.28 3.5 3.6 FPF(%) 49.9 35 32

[0111] In all cases, good performances in terms of fine particle doseare obtained, in particular with 0.3 percent by weight of magnesiumstearate in the final formulation.

EXAMPLES 4 Ordered Mixtures Powder Formulations

[0112] Powders mixtures were prepared by mixing of commerciallyavailable α-lactose monohydrate with different particle size andformoterol fumarate to obtain a ratio of 12 μg of active to 20 mg ofcarrier. Blending was carried out in glass mortar for 30 mins. Theuniformity of distribution of active ingredient and the in-vitro aerosolperformances were determined as previously described. The results arereported In Table 7. TABLE 7 Uniformity of distribution and in-vitroaerosol performances Spherolac 100 Spherolac 100 Spherolac 100Pharmatose 325 M (63-90 μm) (90-150 μm) (150-250 μm) (30-100 μm) Contentuniformity Mean μg) 11.89 11.81 12.98 11.90 RSD (%) 3.88 2.17 9.03 10.10Shot weight Mean (mg) 25.28 25.23 22.02 22.40 RSD (%) 7.73 3.39 6.9322.00 Emitted dose (μg) 11.10 10.30 8.50 7.80 FPD (μg) 1.40 0.70 0.601.20 FPF (%) 12.6 6.8 7.1 15.4

[0113] The results indicate that, upon preparation of ordered mixturescontaining formoterol fumarate as active ingredient according to theteaching of the prior art, the performances of the formulations are verypoor.

EXAMPLE 5 Powders Formulations Containing Different Amounts of FineLactose Particles.

[0114] Carrier A—α-Lactose monohydrate Spherolac 100 (90-150 μm) andSorbolac 400 with a particle size below 30 μm (d(v, 0.5) of about 10 μm)in the ratio 95:5 percent by weight were mixed in a mortar for 15 mins.

[0115] Carrier B—α-Lactose monohydrate Spherolac 100 (90-150 μm) andmicronised lactose (particle size below 5 μm ) in the ratio 95:5 w/wwere mixed in a mortar for 15 mins.

[0116] Carrier C—α-Lactose monohydrate Spherolac 100 (150-250 μm) andSorbolac 400 with a particle size below 30 μm (d(v, 0.5) of about 10 μm)in the ratio 95:5 percent by weight were mixed in a mortar for 30 mins.

[0117] Carrier D—α-Lactose monohydrate Spherolac 100 (150-250 μm) andSorbolac 400 particle size below 30 μm (d(v, 0.5) of about 10 μm) in theratio 90:10 percent by weight were mixed in a mortar for 30 mins.

[0118] In the case of all the formulations tested, the carriers weremixed with formoterol fumarate in mortar for 15 mins to obtain a ratioof 12 μg of active to 25 mg of carrier.

[0119] The results in terms of content uniformity and in-vitro aerosolperformances are reported in Table 8. TABLE 8 Content uniformity andin-vitro aerosol performances Carrier A Carrier B Carrier C Carrier DContent uniformity Mean (μg) 10.96 10.50 11.86 — RSD (%) 1.80 15.01 7.10— Shot weight Mean (mg) 23.46 25.29 25.7 19.53 RSD (%) 51.43 4.19 3.7732.02 Emitted dose (μg) 10.40 9.5 10.1 5.92 FPD (μg) 1.60 2.3 2.3 1.30FPF (%) 15.8 24.4 22.68 21.6

[0120] The results indicate that the performances of such formulationsas well are very poor.

EXAMPLE 6 “Hard-Pellet Formulation Containing Coarse Lactose (PrismaLac40 fraction below 355 μm) and fine lactose”

[0121] α-Lactose monohydrate PrismaLac 40 with a particle size below 355μm and Sorbolac 400 with a particle size below 30 μm (d(v, 0.5) of about10 μm) in the ratio 60:40 percent by weight were first manually agitatedfor 10 mins to promote aggregation and then blended in a Turbula mixerfor 30 mins at 42 r.p.m. The spheronised particles were mixed withformoterol fumarate in a Turbula mixer for 30 mins at 42 r.p.m. toobtain a ratio of 12 μg of active to 15 mg of carrier.

[0122] The results in terms of uniformity of distribution of activeingredient and in-vitro aerosol performances are reported in Table 9.TABLE 9 Uniformity of distribution of active ingredient and in-vitroaerosol performances Spheronised particles Content uniformity Mean (μg)11.90 RSD (%) 18.46 Shot weight Mean (mg) 18.10 RSD (%) 6.80 Emitteddose (μg) 11.10 FPD (μg) 2.10 FPF (%) 18.9

[0123] The results indicate that the formulation without magnesiumstearate has very poor performance.

EXAMPLE 7 Effect of the Addition of Magnesium Stearate by Simple Mixing

[0124] Formulation A—α-Lactose monohydrate Pharmatose 325 M (30 -100 μm)and magnesium stearate in the ratio 99.75:0.25 percent by weight wereblended in a Turbula mixer for 2 hours at 42 r.p.m. The blend was mixedwith formoterol fumarate in a Turbula mixer for 30 mins at 42 r.p.m. toobtain a ratio of 12 μg of active to 25 mg of carrier.

[0125] Formulation B—as reported above but α-Lactose monohydrateSpheroLac 100 (90-150 μm) instead of Pharmatose 325 M.

[0126] Formulation C—α-Lactose monohydrate PrismaLac 40 (with a particlesize below 355 μm) and micronised lactose with a particle size below 5μm in the ratio 40:60 percent by weight were mixed in a Turbula mixerfor 60 mins at 42 r.p.m. 99.75 percent by weight of the resulting blendand 0.25 percent by weight of magnesium stearate were mixed in a Turbulamixer for 60 mins at 42 r.p.m. The resulting blend was finally mixedwith formoterol fumarate in a Turbula mixer for 30 mins at 42 r.p.m. toobtain a ratio of 12 μg of active to 15 mg of carrier.

[0127] Formulation D—Sorbolac 400 with a particle size below 30 μm d(v,0.5) of about 10 μm) and magnesium stearate in the ratio 98: 2 percentby weight were mixed in a high shear mixer for 120 mins (blend A). 85%percent by weight α-lactose monohydrate CapsuLac (212 - 355 μm) and 15%percent by weight of blend A were mixed in Turbula for 2 hours at 42r.p.m. (blend B); the amount of magnesium stearate in the finalformulation is 0.3 percent by weight. Micronised formoterol fumarate wasplaced on the top of blend B and mixed in a Turbula mixer for 10 mins at42 r.p.m. to obtain a ratio of 12 μg of active to 20 mg of carrier.

[0128] Formulation E—Micronized lactose with a particle size below 10 μm(d(v, 0.5) of about 3 μm) and magnesium stearate in the ratio 98: 2percent by weight were mixed in a Sigma Blade mixer for 60 mins (blendA). 85 percent by weight of α-lactose monohydrate CapsuLac (212-355 μm)and 15 percent by weight of blend A were mixed in Turbula for 2 h at 42r.p.m. (blend B); the amount of magnesium stearate in the finalformulation is 0.3 percent by weight. Micronised formoterol fumarate wasplaced on the top of blend B and mixed in a Turbula mixer for 10 mins at42 r.p.m. to obtain a ratio of 12 μg of active to 20 mg of carrier.

[0129] The results in terms of uniformity of distribution of activeingredient and in-vitro aerosol performances are reported in Table 10.TABLE 10 Uniformity of distribution of active ingredient and in-vitroaerosol performances Form- Form- Form- Form- Form- ulations ulationsulations ulations ulations A B C D E Content uniformity Mean (μg) 7.9610.50 9.10 10.68 11.32 RSD (%) 2.16 8.30 24.90 2.80 3.0 Shot weight Mean(mg) 24.10 26.50 12.50 22.07 21.87 RSD (%) 34.60 8.20 15.30 2.50 4.0Emitted dose (μg) 6.10 7.60 9.60 8.60 FPD (μg) 0.60 0.90 1.60 3.38 4.80FPF (%) 9.8 11.8 16.7 39.3 48.37

[0130] Formulations were magnesium stearate is added, by simple mixing,to the total amount of lactose (formulations A-B-C) show very poorperformance; no significant differences in the performance of theformulations were observed using lactose of different particle size.

[0131] Formulations were magnesium stearate is added by a high energymixing to a small amount of fine lactose (blend A of the formulations Dand E) show a significant increase in the performances. In addition, theparticle size of the fine lactose used has a significant effect on thedeaggregation properties of the final formulation; in fact, formulationE prepared using a micronized lactose shows a significant improvedperformance compared with formulation D.

EXAMPLE 8 Effect of the Amount of Micronized Pre-Blend in the FinalFormulation

[0132] αLactose monohydrate SpheroLac 100 (Meggle EP D30) with astarting particle size of 50 to 400 μm (d(v, 0.5) of about 170 μm) andmagnesium stearate with a starting particle size of 3 to 35 μm (d(v,0.5) of about 10 μm) in the ratio 98: 2 percent by weight were co-milledin a jet mill apparatus (blend A) Different ratios of α-lactosemonohydrate Capsulac (212-355 μm) and blend A were placed in a stainlesssteel container and mixed in a Turbula mixer for four hours at 32 r.p.m.(blends B)

[0133] Micronised formoterol fumarate was placed on the top of blends Band mixed in a Turbula mixer for 30 mins at 32 r.p.m. to obtain a ratioof 12 μg of active to 20 mg total mixture. The amount of magnesiumstearate in the final formulation ranges between 0.05 and 0.6 percent byweight.

[0134] The results in terms of uniformity of distribution of activeingredient and in-vitro aerosol performances are reported in Table 11.TABLE 11 Uniformity of distribution of active ingredient and in-vivoaerosol performance Ratio Ratio Ratio Ratio Ratio Ratio 97.5:2.5 95:592.5:7.5 90:10 80:20 70:30 Content uniformity Mean (μg) 11.29 12.2511.53 11.93 11.96 12.00 RSD (%) 3.8 5.7 1.5 2.5 2.0 2.0 Shot weight Mean(mg) 19.27 20.26 20.38 21.05 22.39 22.48 RSD (%) 4.7 3.3 3.2 4.3 3.5 3.7Emitted dose (μg) 10.58 9.20 10.65 9.18 9.63 9.88 FPD (μg) 4.18 5.106.78 5.9 5.33 5.28 FPF (%) 39.4 55.4 63.6 64.3 55.3 53.4

[0135] The results indicate that the performances of all theformulations are good.

EXAMPLE 9 Hard-Pellet Formulation Containing Coarse Lactose (CapsuLac212-355 μm). a Micronized Pre-Blend Lactose/magnesium Stearate Mixtureobtained by Jet Milling and Budesonide as Active Ingredient

[0136] Blends A and B were prepared as described in the Example 1.

[0137] Micronised budesonide was added to the blend B and mixed in aTurbula mixer for 30 mins at 42 r.p.m. to obtain a ratio of 200 μg ofactive to 20 mg of carrier; the amount of magnesium stearate in thefinal formulation is 0.3 percent by weight. The final formulation (hardpellet formulation) was left to stand for 10 mins.

[0138] The results in terms of uniformity of distribution of activeingredient and in-vitro aerosol performances are reported in Table 12.TABLE 12 Uniformity of distribution of active ingredient and in-vitroaerosol performances. Content uniformity Mean (μg) 201.60 RSD (%) 1.60Shot weight Mean (mg) 19.47 RSD (%) 3.90 Emitted dose (μg) 178.10 FPD(μg) 71.6 FPF (%) 40.3

[0139] The results demonstrate that the teaching of the presentinvention could also be applied to the preparation of a powderyformulation of budesonide provided of good performances in term of fineparticle fraction.

EXAMPLE 10 Formulation Containing Lactose 90-150 μm, a MicronizedPre-Blend Lactose/magnesium Stearate Mixture Obtained by Jet Milling andFormoterol as Active Ingredient

[0140] α-Lactose monohydrate SpheroLac 100 (Meggle EP D30) with astarting particle size of 50 to 400 μm (d(v, 0.5) of about 170 μm) andmagnesium stearate with a starting particle size of 3 to 35 μm (d(v,0.5) of about 10 μm) in the ratio 98:2 percent by weight were co-milledin a jet mill apparatus (blend A).

[0141] 92.5 percent by weight of α-lactose monohydrate Spherolac with astarting particle size of 90 to 150 μm (d(v, 0.5 of about 145 μm) and7.5 percent by weight of blend A were placed in a stainless steelcontainer and mixed in a Turbula mixer for four hours at 32 r.p.m.(blends B)

[0142] Micronised formoterol fumarate was placed on the top of blends Band mixed in a Turbula mixer for 30 mins at 32 r.p.m. to obtain a ratioof 12 μg of active to 20 mg total mixture. The amount of magnesiumstearate in the final formulation is 0.15 percent by weight.

[0143] The results in terms of uniformity of distribution of activeingredient and in-vitro aerosol performances are reported in Table 13.TABLE 13 Uniformity of distribution of active ingredient and in-vitroaerosol performances. Content uniformity Mean (μg) 11.75 RSD (%) 1.50Shot weight Mean (mg) — RSD (%) — Emitted dose (μg) — FPD (μg) 5.71 FPF(%) 45.2

[0144] From the reported results, it can be appreciated that, as long asthe fraction of fine particles is less than 10 percent by weight, theperformances of a formulation containing standard lactose as coarsecarrier fraction and a fine particle fraction excipient obtained eitherby co-milling or by co-mixing, are very good.

EXAMPLE 11 Hard-Pellet Formulation Containing Coarse Lactose (Capsulac212-355 μm). A Micronized Pre-Blend Lactose/Magnesium Stearate MixtureObtained by Jet Milling and the Combination Formoterol/BeclometasoneDipropionate (BDP) as Active Ingredient

[0145] Blends A and B were prepared as described in the Example 1.

[0146] Micronised formoterol and BDP were added to the blend B and mixedin a Turbula mixer for 30 mins at 42 r.p.m. to obtain a ratio of 12 μgand 200 μg of active, respectively, to 20 mg of carrier. The amount ofmagnesium stearate in the final formulation is 0.3 percent by weight.The final formulation (hard pellet formulation) was left to stand for 10mins.

[0147] The results in terms of uniformity of distribution of the activeingredients and in-vitro aerosol performances are reported in Table 14.TABLE 14 Uniformity of distribution of the active ingredients andin-vitro aerosol performances. Content uniformity Mean formoterol (μg)11.93 RSD (%) 1.4 Mean BDP (μg) 190.0 RSD (%) 1.1 FPF formoterol (%)47.2 FPF BDP (%) 40.4

[0148] The results indicate that, even in presence of a combination ofactive ingredients, the performances of the formulation are very good.

Example 12 Effect of the Time of Mixing

[0149] Different blends were prepared by co-mixing CapsuLac 212-355 μm,micronized lactose with a particle size below 10 μm (d(v, 0.5) of about3μm) and magnesium stearate in the ratio 89.8:10:0.2 percent by weight,in a Turbula mixer (32 r.p.m.) at increasing mixing time (1, 2 and 4hours).

[0150] Micronised formoterol fumarate was placed on the top of eachblend and mixed in a Turbula mixer for 30 mins at 32 r.p.m. to obtain aratio of 12 μg of active to 20 mg total mixture.

[0151] The results in terms of fine particle fraction (FPF) are reportedin Table 15. TABLE 15 Effect of the mixing time on FPF Time of mixingFine particle fraction (%) 1 hour 21.0 2 hours 34.2 4 hours 40.5

[0152] The results indicate that good performances in terms of fineparticle fraction are achieved after mixing for at least two hours.

1. A powder for use in a dry powder inhaler, the powder comprising i) afraction of fine particle size constituted of a mixture of aphysiologically acceptable excipient and magnesium stearate, the mixturehaving a mean particle size of less than 35 μm; ii) a fraction of coarseparticles constituted of a physiologically acceptable carrier having aparticle size of at least 100 μm, said mixture (i) being composed of 90to 99 percent by weight of particles of excipient and 1 to 10 percent byweight of magnesium stearate and the ratio between the fine excipientparticles and the coarse carrier particles being between 1:99 and 40:60percent by weight; and the said mixture having been further mixed withone or more active ingredient in micronised form selected frombudesonide and its epimers, formoterol, TA 2005 and its stereoisomers,their salts and their combination.
 2. A powder according to claim 1wherein the active ingredient is the 22 R epimer of budesonide.
 3. Apowder according to claim 1 wherein the active ingredient is acombination of formoterol or TA-2005 with a corticosteroid selected frombudesonide and its epimers and beclometasone dipropionate.
 4. A powderaccording to claims 1-3, wherein the magnesium stearate particlespartially coat the surface of either the excipient particles and thecoarse carrier particles.
 5. A powder according to claims 1-4, whereinthe particle size of the fraction of fine particle size is less than 15μm.
 6. A powder according to claims 1-5 characterized in that thefraction of coarse carrier particles has a particle size of at least 175μm, the fraction of fine particle size is composed of 98 percent byweight of particles of excipient and 2 percent by weight of magnesiumstearate and the ratio between the fine excipient particles and thecoarse carrier particles is 10:90 percent by weight.
 7. A powderaccording to claims 1-6 wherein the coarse carrier particles have a“fissure index” of at least 1.25
 8. A powder according to any precedingclaim wherein the physiological acceptable excipient is one or morecrystalline sugars.
 9. A powder according to any preceding claim whereinthe the physiological acceptable excipient is α-lactose monohydrate. 10.A process for making a powder according to claims 1-9, said processincluding the steps of: a) co-micronising the excipient particles andthe magnesium stearate particles such that to significantly reduce theirparticle size and contemporaneously making the magnesium stearateparticles coating the surface of the excipient particles; b)spheronising by mixing the resulting mixture with the coarse carrierparticles such that mixture particles adhere to the surface of thecoarse carrier particle; c) adding by mixing the active particles in themicronized form to the spheronised particles.
 11. A process according toclaim 10 wherein step a) is carried out by milling preferably by using ajet mill.
 12. A process for making a powder according to claims 1-9,said process including the steps of: a) mixing in high-energy mixer theexcipient particles of a starting particle size less than 35 μm and themagnesium stearate particles in such a way as to make the magnesiumstearate particles partially coating the surface of the excipientparticles; b) spheronising by mixing the resulting mixture with thecoarse carrier particles such that mixture particles adhere to thesurface of the coarse carrier particles; c) adding by mixing the activeparticles in the micronised form to the spheronised particles.
 13. Aprocess according to claim 12 wherein the excipient particles of step a)have a starting particle size of less than 15 μm.
 14. A process ofmaking a powder according to claims 1-9, said process including thesteps of a) co-mixing the coarse carrier particles, magnesium stearateand the fine excipient particles; b) adding by mixing the activeparticles in the micronised form to the mixture wherein the fraction ofcoarse carrier particles has a particle size of at least 175 μm and theco-mixing a) is carried for at least two hours.